tbuckley/cabot-search huggingface dataset:
Overcoming Taxane Resistance: Preclinical and Phase 1 Studies of Relacorilant, a Selective Glucocorticoid Receptor Modulator, with Nab-Paclitaxel in Solid Tumors
Authors: Pamela N. Munster, Andrew E. Greenstein, Gini F. Fleming, Erkut Borazanci, Manish R. Sharma, Joseph M. Custodio, Iulia Cristina Tudor, Hristina I. Pashova, Stacie Peacock Shepherd, Andreas Grauer, Jasgit C. Sachdev
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Chemotherapy resistance remains a major problem in many solid tumors, including breast, ovarian, and pancreatic cancer. Glucocorticoids are one potential driver of chemotherapy resistance as they can mediate tumor progression via induction of cell-survival pathways. We investigated whether combining the selective glucocorticoid receptor (GR) modulator relacorilant with taxanes can enhance antitumor activity. Patients and Methods: The effect of relacorilant on paclitaxel efficacy was assessed in OVCAR5 cells in vitro and in the MIA PaCa-2 xenograft. A phase 1 study of patients with advanced solid tumors was conducted to determine the recommended phase 2 dose of relacorilant + nab-paclitaxel. Results: In OVCAR5 cells, relacorilant reversed the deleterious effects of glucocorticoids on paclitaxel efficacy (P &amp;lt; 0.001). Compared with paclitaxel alone, relacorilant + paclitaxel reduced tumor growth and slowed time to progression in xenograft models (both P &amp;lt; 0.0001). In the heavily pretreated phase 1 population [median (range) of prior regimens: 3 (1–8), prior taxane in 75.3% (55/73)], 33% (19/57) of response-evaluable patients achieved durable disease control (≥16 weeks) with relacorilant + nab-paclitaxel and 28.6% (12/42) experienced longer duration of benefit than on prior taxane (up to 6.4×). The most common dose-limiting toxicity of the combination was neutropenia, which was manageable with prophylactic G-CSF. Clinical benefit with relacorilant + nab-paclitaxel was also associated with GR-regulated transcript-level changes in a panel of GR-controlled genes. Conclusions: The observed preclinical, clinical, and GR-specific pharmacodynamic responses demonstrate that selective GR modulation with relacorilant combined with nab-paclitaxel may promote chemotherapy response and is tolerable. Further evaluation of this combination in tumor types responsive to taxanes is ongoing.
Comparison of Power Training vs Traditional Strength Training on Physical Function in Older Adults
Authors: Anoop T. Balachandran, James Steele, Daniel Angielczyk, Mark Belio, Brad J. Schoenfeld, Norberto Quiles, Nicole Askin, Ahmed M. Abou-Setta
Journal: JAMA Network Open (2022)

Strength training exercise is recommended for improving physical function in older adults. However, whether strength training (lifting and lowering weights under control) and power training (PT) (lifting weights fast and lowering under control) are associated with improved physical function in older adults is not clear.To evaluate whether PT vs traditional strength training is associated with physical function improvement in older adults.Systematic searches of MEDLINE, Embase, Cochrane Central, CINAHL, PsycInfo, PEDro, and SPORTDiscus were conducted from database inception to October 20, 2021.Randomized clinical trials (RCTs) that compared strength training with instructions to move the weight as fast as possible in the lifting phase with traditional strength training in healthy, community-living older adults (age ≥60 years).Two authors independently selected trials, extracted data, assessed the risk of bias using the Cochrane risk-of-bias tool 2, and assessed the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. Summary effect size measures were calculated using a multilevel random-effects model with cluster robust variance estimation and are reported as standardized mean differences (SMDs). Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline.Primary outcomes included physical function and self-reported physical function. Secondary outcomes included power, strength, muscle mass, walk speed, balance, and adverse effects.A total of 20 RCTs enrolling 566 community-living older adults (mean [SD] age, 70.1 [4.8] years; 368 [65%] women) were included. For the primary outcomes, PT was associated with an improvement in physical function with low-certainty evidence in 13 RCTs (n = 383) (SMD, 0.30; 95% CI, 0.05-0.54) and self-reported function with low-certainty evidence in 3 RCTs (n = 85) (SMD, 0.38; 95% CI, -0.62 to 1.37). The evidence was downgraded by 2 levels for high risk of bias and imprecision for physical function and very serious imprecision for self-reported physical function.In this systematic review and meta-analysis, PT was associated with a modest improvement in physical function compared with traditional strength training in healthy, community-living older adults. However, high-quality, larger RCTs are required to draw more definitive conclusions.
Changes in cardiac biomarkers in association with alterations in cardiac structure and function, and health status in heart failure with reduced ejection fraction: <scp>the EVALUATE‐HF trial</scp>
Authors: Peder L. Myhre, Brian L. Claggett, Amil M. Shah, Margaret F. Prescott, Jonathan H. Ward, James C. Fang, Gary F. Mitchell, Scott D. Solomon, Akshay S. Desai
Journal: European Journal of Heart Failure (2022)
Prolonged blood circulation outperforms active targeting for nanocarriers-mediated enhanced hepatocellular carcinoma therapy in vivo
Authors: Yue-Qing Wang, Cong Huang, Peng-Ju Ye, Jin-Rong Long, Cheng-Hu Xu, Ying Liu, Xiao-Li Ling, Shao-Yang Lv, Dong-Xiu He, Hua Wei, Cui-Yun Yu
Journal: Journal of Controlled Release (2022)
Is Rheumatoid Arthritis a Causal Factor in Cardiovascular Disease?
Authors: S. Louis Bridges, Timothy B. Niewold, Tony R. Merriman
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Artificial intelligence for the prevention and clinical management of hepatocellular carcinoma
Authors: Julien Calderaro, Tobias Paul Seraphin, Tom Luedde, Tracey G. Simon
Journal: Journal of Hepatology (2022)

Hepatocellular carcinoma (HCC) currently represents the fifth most common malignancy and the third-leading cause of cancer-related death worldwide, with incidence and mortality rates that are increasing. Recently, artificial intelligence (AI) has emerged as a unique opportunity to improve the full spectrum of HCC clinical care, by improving HCC risk prediction, diagnosis, and prognostication. AI approaches include computational search algorithms, machine learning (ML) and deep learning (DL) models. ML consists of a computer running repeated iterations of models, in order to progressively improve performance of a specific task, such as classifying an outcome. DL models are a subtype of ML, based on neural network structures that are inspired by the neuroanatomy of the human brain. A growing body of recent data now apply DL models to diverse data sources - including electronic health record data, imaging modalities, histopathology and molecular biomarkers - to improve the accuracy of HCC risk prediction, detection and prediction of treatment response. Despite the promise of these early results, future research is still needed to standardise AI data, and to improve both the generalisability and interpretability of results. If such challenges can be overcome, AI has the potential to profoundly change the way in which care is provided to patients with or at risk of HCC.
Microdissection Testicular Sperm Extraction Versus Multiple Needle-pass Percutaneous Testicular Sperm Aspiration in Men with Nonobstructive Azoospermia: A Randomized Clinical Trial
Authors: Christian Fuglesang S. Jensen, Dana A. Ohl, Mikkel Fode, Niels Jørgensen, Aleksander Giwercman, Niels Henrik Bruun, Angel Elenkov, Anna Klajnbard, Claus Y. Andersen, Lise Aksglaede, Marie Louise Grøndahl, Mette C. Bekker, Jens Sønksen
Journal: European Urology (2022)
EULAR points to consider for therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases
Authors: Charlotte LM Krieckaert, Astrid van Tubergen, Johanna Elin Gehin, Borja Hernández-Breijo, Guillaume Le Mélédo, Alejandro Balsa, Peter Böhm, Sasa Cucnik, Ori Elkayam, Guro L Goll, Femke Hooijberg, Meghna Jani, Patrick DW Kiely, Neil McCarthy, Denis Mulleman, Victoria Navarro-Compán, Katherine Payne, Martin E Perry, Chamaida Plasencia-Rodriguez, Simon R Stones, Silje Watterdal Syversen, Annick de Vries, Katherine M Ward, Gertjan Wolbink, John D Isaacs
Journal: Annals of the Rheumatic Diseases (2022)

Objective To develop EULAR points-to-consider for therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases (RMDs). Methods The points-to-consider were developed in accordance with EULAR standardised operation procedures by a multidisciplinary task force from eight European countries, based on a systematic literature review and expert consensus. Level of evidence and strength of the points-to-consider were determined, and mean levels of agreement among the task force were calculated using a 10-point rating scale. Results Six overarching principles and 13 points-to-consider were formulated. The level of agreement among the task force for the overarching principles and points-to-consider ranged from 8.4 to 9.9.The overarching principles define TDM and its subtypes, and reinforce the underlying pharmacokinetic/pharmacodynamic principles, which are relevant to all biopharmaceutical classes. The points-to-consider highlight the clinical utility of the measurement and interpretation of biopharmaceutical blood concentrations and antidrug antibodies in specific clinical scenarios, including factors that influence these parameters. In general, proactive use of TDM is not recommended but reactive TDM could be considered in certain clinical situations. An important factor limiting wider adoption of TDM is the lack of both high quality trials addressing effectiveness and safety of TDM and robust economic evaluation in patients with RMDs. Future research should focus on providing this evidence, as well as on further understanding of pharmacokinetic and pharmacodynamic characteristics of biopharmaceuticals. Conclusion These points-to-consider are evidence-based and consensus-based statements for the use of TDM of biopharmaceuticals in inflammatory RMDs, addressing the clinical utility of TDM.
Small‐molecule inhibitors of cyclophilin D as potential therapeutics in mitochondria‐related diseases
Authors: Annamaria Haleckova, Ondrej Benek, Lucie Zemanová, Rafael Dolezal, Kamil Musilek
Journal: Medicinal Research Reviews (2022)

Abstract Cyclophilin D (CypD) is a key regulator of mitochondrial permeability transition pore (mPTP) opening. This pathophysiological phenomenon is associated with the development of several human diseases, including ischemia‐reperfusion injury and neurodegeneration. Blocking mPTP opening through CypD inhibition could be a novel and promising therapeutic approach for these conditions. While numerous CypD inhibitors have been discovered to date, none have been introduced into clinical practice, mostly owing to their high toxicity, unfavorable pharmacokinetics, and low selectivity for CypD over other cyclophilins. This review summarizes current knowledge of CypD inhibitors, with a particular focus on small‐molecule compounds with regard to their in vitro activity, their selectivity for CypD, and their binding mode within the enzyme's active site. Finally, approaches for improving the molecular design of CypD inhibitors are discussed.
Retinoic acid signaling acts as a rheostat to balance Treg function
Authors: Govindarajan Thangavelu, Gabriela Andrejeva, Sara Bolivar-Wagers, Sujeong Jin, Michael C. Zaiken, Michael Loschi, Ethan G. Aguilar, Scott N. Furlan, Chrysothemis C. Brown, Yu-Chi Lee, Cameron McDonald Hyman, Colby J. Feser, Angela Panoskaltsis-Mortari, Keli L. Hippen, Kelli P. MacDonald, William J. Murphy, Ivan Maillard, Geoffrey R. Hill, David H. Munn, Robert Zeiser, Leslie S. Kean, Jeffrey C. Rathmell, Hongbo Chi, Randolph J. Noelle, Bruce R. Blazar
Journal: Cellular and Molecular Immunology (2022)
Effect of moderate-to-severe hepatic steatosis on neutralising antibody response among BNT162b2 and CoronaVac recipients
Authors: Ka Shing Cheung, Lok Ka Lam, Rex Wan Hin Hui, Xianhua Mao, Ruiqi R Zhang, Kwok Hung Chan, Ivan FN Hung, Wai Kay Seto, Man-Fung Yuen
Journal: Clinical and Molecular Hepatology (2022)

Studies of hepatic steatosis (HS) effect on COVID-19 vaccine immunogenicity are lacking. We aimed to compare immunogenicity of BNT162b2 and CoronaVac among moderate/severe HS and control subjects.Two hundred ninety-five subjects who received BNT162b2 or CoronaVac vaccines from five vaccination centers were categorized into moderate/severe HS (controlled attenuation parameter ≥268 dB/m on transient elastography) (n=74) or control (n=221) groups. Primary outcomes were seroconversion rates of neutralising antibody by live virus Microneutralization (vMN) assay (titer ≥10) at day21 (BNT162b2) or day28 (CoronaVac) and day56 (both). Secondary outcome was highest-tier titer response (top 25% of vMN titer; cutoff: 160 [BNT162b2] and 20 [CoronaVac]) at day 56.For BNT162b2 (n=228, 77.3%), there was no statistical differences in seroconversion rates (day21: 71.7% vs. 76.6%; day56: 100% vs. 100%) or vMN geometric mean titer (GMT) (day21: 13.2 vs. 13.3; day56: 91.9 vs. 101.4) among moderate/severe HS and control groups respectively. However, lower proportion of moderate/severe HS patients had highest-tier response (day56: 5.0% vs. 15.5%; P=0.037). For CoronaVac (n=67, 22.7%), there was no statistical differences in seroconversion rates (day21: 7.1% vs. 15.1%; day56: 64.3% vs. 83.0%) or vMN GMT (5.3 vs. 5.8,) at day28. However, moderate/severe HS patients had lower vMN GMT (9.1 vs. 14.8, P=0.021) at day 56 with lower proportion having highest-tier response (21.4% vs. 52.8%, P=0.036).While there was no difference in seroconversion rate between moderate/severe HS and control groups after two doses of vaccine, a lower proportion of moderate/severe HS patients achieved highest-tier response for either BNT162b2 or CoronaVac.
Host cells subdivide nutrient niches into discrete biogeographical microhabitats for gut microbes
Authors: Megan J. Liou, Brittany M. Miller, Yael Litvak, Henry Nguyen, Dean E. Natwick, Hannah P. Savage, Jordan A. Rixon, Scott P. Mahan, Hirotaka Hiyoshi, Andrew W.L. Rogers, Eric M. Velazquez, Brian P. Butler, Sean R. Collins, Stephen J. McSorley, Rasika M. Harshey, Mariana X. Byndloss, Scott I. Simon, Andreas J. Bäumler
Journal: Cell Host & Microbe (2022)

Changes in the microbiota composition are associated with many human diseases, but factors that govern strain abundance remain poorly defined. We show that a commensal Escherichia coli strain and a pathogenic Salmonella enterica serovar Typhimurium isolate both utilize nitrate for intestinal growth, but each accesses this resource in a distinct biogeographical niche. Commensal E. coli utilizes epithelial-derived nitrate, whereas nitrate in the niche occupied by S. Typhimurium is derived from phagocytic infiltrates. Surprisingly, avirulent S. Typhimurium was shown to be unable to utilize epithelial-derived nitrate because its chemotaxis receptors McpB and McpC exclude the pathogen from the niche occupied by E. coli. In contrast, E. coli invades the niche constructed by S. Typhimurium virulence factors and confers colonization resistance by competing for nitrate. Thus, nutrient niches are not defined solely by critical resources, but they can be further subdivided biogeographically within the host into distinct microhabitats, thereby generating new niche opportunities for distinct bacterial species.
Experimental studies of bias: Imperfect but neither useless nor unique
Authors: Callie H. Burt, Brian B. Boutwell
Journal: Behavioral and Brain Sciences (2022)

Abstract Cesario provides a compelling critique of the use of experimental social psychology to explain real-world group disparities. We concur with his targeted critique and extend “the problem of missing information” to another common measures of bias. We disagree with Cesario's broader argument that the entire enterprise be abandoned, suggesting instead targeted utilization. Finally, we question whether the critique is appropriately directed at experimental social psychologists.
Transcriptional profiling of macrophages in situ in metastatic melanoma reveals localization-dependent phenotypes and function
Authors: Jan Martinek, Jianan Lin, Kyung In Kim, Victor G. Wang, Te-Chia Wu, Michael Chiorazzi, Hannah Boruchov, Ananya Gulati, Shamreethaa Seeniraj, Lili Sun, Florentina Marches, Paul Robson, Anthony Rongvaux, Richard A. Flavell, Joshy George, Jeffrey H. Chuang, Jacques Banchereau, Karolina Palucka
Journal: Cell Reports Medicine (2022)

Modulation of immune function at the tumor site could improve patient outcomes. Here, we analyze patient samples of metastatic melanoma, a tumor responsive to T cell-based therapies, and find that tumor-infiltrating T cells are primarily juxtaposed to CD14+ monocytes/macrophages rather than melanoma cells. Using immunofluorescence-guided laser capture microdissection, we analyze transcriptomes of CD3+ T cells, CD14 + monocytes/macrophages, and melanoma cells in non-dissociated tissue. Stromal CD14+ cells display a specific transcriptional signature distinct from CD14+ cells within tumor nests. This signature contains LY75, a gene linked with antigen capture and regulation of tolerance and immunity in dendritic cells (DCs). When applied to TCGA cohorts, this gene set can distinguish patients with significantly prolonged survival in metastatic cutaneous melanoma and other cancers. Thus, the stromal CD14+ cell signature represents a candidate biomarker and suggests that reprogramming of stromal macrophages to acquire DC function may offer a therapeutic opportunity for metastatic cancers.
What next? Expanding our view of city planning and global health, and implementing and monitoring evidence-informed policy
Authors: Billie Giles-Corti, Anne Vernez Moudon, Melanie Lowe, Ester Cerin, Geoff Boeing, Howard Frumkin, Deborah Salvo, Sarah Foster, Alexandra Kleeman, Sarah Bekessy, Thiago Hérick de Sá, Mark Nieuwenhuijsen, Carl Higgs, Erica Hinckson, Deepti Adlakha, Jonathan Arundel, Shiqin Liu, Adewale L Oyeyemi, Kornsupha Nitvimol, James F Sallis
Journal: The Lancet Global Health (2022)

This Series on urban design, transport, and health aimed to facilitate development of a global system of health-related policy and spatial indicators to assess achievements and deficiencies in urban and transport policies and features. This final paper in the Series summarises key findings, considers what to do next, and outlines urgent key actions. Our study of 25 cities in 19 countries found that, despite many well intentioned policies, few cities had measurable standards and policy targets to achieve healthy and sustainable cities. Available standards and targets were often insufficient to promote health and wellbeing, and health-supportive urban design and transport features were often inadequate or inequitably distributed. City planning decisions affect human and planetary health and amplify city vulnerabilities, as the COVID-19 pandemic has highlighted. Hence, we offer an expanded framework of pathways through which city planning affects health, incorporating 11 integrated urban system policies and 11 integrated urban and transport interventions addressing current and emerging issues. Our call to action recommends widespread uptake and further development of our methods and open-source tools to create upstream policy and spatial indicators to benchmark and track progress; unmask spatial inequities; inform interventions and investments; and accelerate transitions to net zero, healthy, and sustainable cities.
Inspire
Authors: Michael K. Harty
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Kinome-wide polypharmacology profiling of small molecules by multi-task graph isomorphism network approach
Authors: Lingjie Bao, Zhe Wang, Zhenxing Wu, Hao Luo, Jiahui Yu, Yu Kang, Dongsheng Cao, Tingjun Hou
Journal: Acta Pharmaceutica Sinica B (2022)

Prediction of the interactions between small molecules and their targets play important roles in various applications of drug development, such as lead discovery, drug repurposing and elucidation of potential drug side effects. Therefore, a variety of machine learning-based models have been developed to predict these interactions. In this study, a model called auxiliary multi-task graph isomorphism network with uncertainty weighting (AMGU) was developed to predict the inhibitory activities of small molecules against 204 different kinases based on the multi-task Graph Isomorphism Network (MT-GIN) with the auxiliary learning and uncertainty weighting strategy. The calculation results illustrate that the AMGU model outperformed the descriptor-based models and state-of-the-art graph neural networks (GNN) models on the internal test set. Furthermore, it also exhibited much better performance on two external test sets, suggesting that the AMGU model has enhanced generalizability due to its great transfer learning capacity. Then, a naïve model-agnostic interpretable method for GNN called edges masking was devised to explain the underlying predictive mechanisms, and the consistency of the interpretability results for 5 typical epidermal growth factor receptor (EGFR) inhibitors with their structure‒activity relationships could be observed. Finally, a free online web server called KIP was developed to predict the kinome-wide polypharmacology effects of small molecules (http://cadd.zju.edu.cn/kip).
Abstract B033: Immunosuppressive niche engineering at the onset of human colorectal cancer
Authors: Chandler D. Gatenbee, Ann-Marie Baker, Ryan O. Schenck, Maximilian Strobl, Jeffrey West, Mark Robertson-Tessi, Trevor A. Graham, Alexander R.A. Anderson
Journal: Cancer Research (2022)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR0081) of the Conference Proceedings. Citation Format: Chandler D. Gatenbee, Ann-Marie Baker, Ryan O. Schenck, Maximilian Strobl, Jeffrey West, Mark Robertson-Tessi, Trevor A. Graham, Alexander R.A. Anderson. Immunosuppressive niche engineering at the onset of human colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B033.